Click-Dimerized Cinchona Alkaloids

Article abstract of DOI:10.1021/acs.joc.6b01403

A series of Cinchona alkaloid-derived dimers were obtained in high yields in copper-catalyzed 1,3-dipolar click cycloaddition using bis(TMS)butadiyne and other bivalent alkynes. The products with bitriazole linkers were effective ligands for asymmetric copper-catalyzed Michael addition. It was shown that the presence of such linker was responsible for effective chirality transfer.

Full text of DOI:10.1021/acs.joc.6b01403

Note
pubs.acs.org/joc
Click-Dimerized Cinchona Alkaloids
Przemysław J. Boratynski* and Rafał Kowalczyk
́
́
Department of Organic Chemistry, Wrocław University of Technology, Wyspianskiego 27, Wrocław 50-370, Poland
S
* Supporting Information
ABSTRACT: A series of Cinchona alkaloid-derived dimers
were obtained in high yields in copper-catalyzed 1,3-dipolar
“click” cycloaddition using bis(TMS)butadiyne and other
bivalent alkynes. The products with bitriazole linkers were
effective ligands for asymmetric copper-catalyzed Michael
addition. It was shown that the presence of such linker was
responsible for effective chirality transfer.
ynthetic dimeric Cinchona alkaloids,1 and in particular the
1,3-butadiyne.21 Since the double cycloaddition products were
expected to form coordination compounds with copper, the
reaction was terminated by the addition of aqueous sodium
sulfide, which helped remove most of the metal from the
reaction mixture during workup.
2−4
SSharpless dihydroxylation ligands
have found wide use
in enantioselective synthesis. Their versatile applications
include both metal-catalyzed reactions and organocatalysis.1−5
In these dimers the alkaloid residues are connected via an ether
bond with a heterocyclic linker. The length of the linker (5−6
atoms between C9 centers) determines the size of the cavity
and translates to enantioselective performance.
The reactions of epi-azido quinine (eQN-1) with dialkynes
proceeded and the expected very good yields were obtained
(Scheme 1). The less congested products were obtained nearly
quantitatively, whereas the much more sterically demanding
transformations of 1,2-diethynyl-benzene and 1,8-diethynyl-
naphthalene derivatives were still very efficient (91−96% per
cyclization step). In most cases chromatography was needed to
remove the excess of one of the applied reagents. Only the
isolation of eQN-6 required careful separation from additional
byproducts. More bitriazole dimer 2 analogues were obtained
from other Cinchona alkaloid 9-azides (Table 1). However, in
case of azides of 8R,9S configuration (DHQD-1 and DHCN-
1), derived from dihydroquinidine and dihydrocinchonine,22
the dimeric products 2 were obtained in rather low yields (47
and 22%, respectively). This observation is correlated with
poorer accessibility of the 9-substituent in the quinidine
derivatives due to steric interactions also observed for other
transformations of the alkaloids.
Another concept significantly developed by Sharplessclick-
chemistryusing copper-catalyzed azide alkyne cycloaddition
(CuAAC)6−8 has been proven as an efficient way of
conjugating molecules relevant to many areas of biomedical
research.9 Most often, however, the lone triazole linker unit has
little further use. In contrast, a combination of triazole with
another heterocycle gives systems of rich coordination
chemistry.10 The use of bifunctional components of CuAAC
to make dimeric compounds has been exploited to some
extent.11,12 Also, molecules with more than one triazole unit
have been used as N,N-donating ligands,13 dicarbene ligands,14
and as anion binders.15 Here we report an application of click-
chemistry to obtain a new class of C2-symmetric dimeric
Cinchona alkaloids with triazole-based linkers.
The Cinchona alkaloid 9-azides 1 were conveniently prepared
using a known two-step procedure involving SN2 substitution of
respective alkaloid 9-methanesulfonate with sodium azide.16
Consequently, azides of epi configuration (i.e., 8S,9S or 8R,9R),
eQN-1, eCD-1, and eDHQD-1, were obtained starting from
quinine, cinchonidine, and 10,11-dihydroquinidine, while azides
of native configuration (i.e., 8S,9R or 8R,9S), QN-1, DHQD-1,
and DHCN-1, were obtained from epi-quinine, epi-10,11-
dihydroquinidine, and epi-10,11-dihydrocinchonine, respec-
tively. Alternatively, the azides could be obtained in just one
step via the Mitsunobu reaction.17 On the other hand, the
bivalent terminal alkynes or their TMS-protected derivatives
were commercially available or could be obtained from the
respective aryl halides and TMS-acetylene in the Sonogashira
reactions.18−20 For convenience, the TMS groups were not
removed from the terminal alkynes prior to the coupling
reaction, instead a one pot procedure was applied (Scheme 1).
Moreover, such approach alleviated the need to handle instable
In order to obtain monomeric analogue of eQN-2, the
alkaloid 9-azide was reacted with an excess of TMS-acetylene
under CuAAC conditions. The reaction proceeded with
excellent yield and the products were obtained in high purity
directly after workup. The TMS group was removed with dilute
HF in water/MeOH.
The shortest link between the alkaloid units was constructed
from 1,3-butadiyne derivative. The overall length (6 atoms in
between the C-9 centers) is the same as in the Sharpless-type
aryl ethers (Figure 1). The bitriazole linker is expected to adopt
a planar conformation to ensure best orbital overlapping
between the two 1,2,3-triazole units. Although there are two
conformations of this system, the anti conformation is
significantly lower in energy (ca. 6 kcal/mol by DFT
Received: June 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Synthesis of Quinine Click Dimers
Table 1. Synthesis of Bitriazole Dimers 2
alkaloid azide core, 1
R6′
R3
configuration
product
yield
epi-quinine
OCH3
OCH3
OCH3
OCH3
H
C2H3
C2H3
Et
8S,9S
8S,9R
8R,9R
8R,9S
8S,9S
8R,9S
eQN-2
88
74
78
47
67
22
nat-quininie
QN-2
epi-dihydroquinidine
nat-dihydroquinidine
epi-cinchonidine
nat-dihydrocinchonine
eDHQD-2
DHQD-2
eCD-2
Et
C2H3
Et
H
DHCN-2
calculation). However, the syn conformation is expected to be
prevalent when complexed with metal ions or protonated. The
DFT calculations at the B3LYP/CC-pVDZ level of theory for
the gas phase suggest that C2-symmetric conformation is
overall lowest in energy (Figure 2). The N−C9−C8−N and
N−C9−C4′−C3′diahedral angles were +44.3° and −18.8°,
respectively. In this anti-open conformation the two quinucli-
dine nitrogen face each other at a distance of about 8 Å, while
another cavity between the two nearly parallel quinoline rings
measures ca. 8.5 Å. The well resolved NMR spectra for eQN-2
as well as good correlation of experimental 1H and 13C
chemical shifts and DFT calculated isotropic shieldings (see SI)
B
DOI: 10.1021/acs.joc.6b01403
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The Journal of Organic Chemistry
Note
Scheme 2. Synthesis of Triazolyl-quinine eQN-8
and copper(II) triflate run in dichloromethane, yielded 62% of
product 10 in an enantioselective manner (e.r. 87:13; Table 2).
Table 2. Application of Dimeric Cinchona Alkaloids in
Copper-Catalyzed Asymmetric Michael Addition
Figure 1. Comparison of Sharpless ligand and QN-2.
entry
ligand (10 mol %)
e.r. (R:S)
1
2
3
4
5
6
7
8
eQN-2
87:13
52:48
51:49
52:48
49:51
57:43
50:50
51:49
53:47
63:37
59:41
82:18
21:79
49:51
eQN-3
eQN-4
eQN-5
eQN-6
eQN-8
(QN)2PHAL
quinine
eQN-2
a
9
b
Figure 2. Lowest energy conformer of eQN-2 optimized at the DFT/
B3LYP/CC-pVDZ level of theory.
10
eQN-2
11
12
13
14
QN-2
eCD-2
eDHQD-2
DHQD-2
suggest that the conformation is prevalent in solution. In
contrast, dimers with extended linkers, eQN-3, eQN-4, and
particularly eQN-6, display broadened spectra. In the case of
1,8-bis(triazolyl)naphthalene system in eQN-6, the planar
orientation is no longer possible and high congestion constricts
rotation along a few single bonds resulting in complex
conformation equilibria and 1H NMR spectral changes
observed between 45 and −45 °C (Figure S12, SI).
The obtained dimers 2 are analogous to the Sharpless ligands
(Figure 1) of a proven very broad application scope in
catalysis.1,4 On the other hand, new metal chelating sites within
bitriazole (2) and ditriazolyl-aryl (3 to 6) units are reminiscent
of C2-symmetric BOX-ligands.23 Both these structural
similarities within the obtained ligands are of relevance to
asymmetric catalysis. However, there is little data13 on such
application of bitriazole systems. The attempted osmium-
catalyzed dihydroxylation of stilbene and aminohydroxylation
of ethyl cinammate in the presence of eQN-2 led to marginal or
no product formation. However, the bitriazole is known to
coordinate copper(II),10 and the formed complex could further
bind dicarbonyl compounds. Thus, the alkaloid dimers were
investigated in the copper-mediated asymmetric Michael
addition. For catalytic assay, ethyl (E)-2-oxo-4-phenyl-3-
butenoate (9) was chosen as a Michael acceptor.24 Its reaction
with 1,3-dicarbonyl compounds results in two sequential
additions giving a cyclic hemiacetal 1025−30 (Scheme 2). This
heterocyclic product shares framework with many natural
compounds31−33 and is an attractive intermediate.34
a
b
Without copper salt. Ligand to metal ratio 2:1.
The process was very sensitive to the transition metal salt used,
and the best results were obtained with copper triflate (for the
details, see SI). Triazole ligands with spacers, eQN-3 through
eQN-6, failed to transfer chirality to the product 10 (Table 2,
entries 2−6). Also the application of analogous monomeric
triazole derivative eQN-8 led to racemate. Similairly, the
complexes of Sharpless asymmetric dihydroxylation ligands
with phthalazine ((QN)2PHAL) and anthraquinone cores were
ineffective, providing nearly racemic product (ee up to 11%).
Thus, the reaction clearly requires the bitriazole system. The
tested reaction can also be catalyzed with a base. Consequently,
the presence of basic sites25 in bare ligand eQN-2 results in
organocatalyzed process in the absence of copper, however the
reaction proceeds without stereoselection (Table 2, entry 9).
Also the use of higher ligand to metal ratio (i.e., 2:1) resulted in
a significantly deteriorated selectivity.
The relative configuration at C8 and C9 stereogenic centers
in the Cinchona dimers 2 determines the structure by differently
arranging basic quinuclidine sites and sterically shielding
quinoline rings around the bitriazole-bound metal center,
thus translated to a pronounced effect on enantioselectivity.
Dimers of 9-epi configuration (8S,9S and 8R,9R) provided high
enantiomeric excess, whereas ligands with 9-native config-
uration (8S,9R and 8R,9S) gave at most 18 %ee (Table 2,
entries 1 and 13 vs entries 11 and 14). On the other hand, the
choice of pseudoenantiomeric catalysts, eQN-2 (8S,9S) and
The Michael reaction of 9 and dimedone, catalyzed by 10
mol% of complex formed in situ from bitriazole dimer eQN-2
C
DOI: 10.1021/acs.joc.6b01403
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The Journal of Organic Chemistry
Note
1,1′-Di((8S,9R)-6′-methoxycinchonan-9-yl)-4,4′-bi-1,2,3-tria-
zole (QN-2). Following the general procedure, starting from 9R-azido-
9-deoxyquinine (QN-1, 436 mg, 1.25 mmol), 346 mg of product
(74%) was obtained after chromatography (CHCl3/MeOH 20:1 v/v)
eDHQD-2 (8R,9R), allowed for both antipodes of 10 to be
obtained in similar enantioselectivity. The use of quinine and
cinchonidine-derived dimers, eQN-2 and eCD-2, led to very
similar enantioselectivity (e.r. 87:13 vs 82:18, respectively), thus
indicating minor influence of the 6′-methoxy groups.
In the Michael reaction catalyzed by eQN-2/Cu(OTf)2, the
change of the nucleophile from dimedone to 1,3-cyclo-
hexanedione provided the corresponding product (R)-11 with
slightly improved enantioselectivity (Scheme 3). However, the
application of other (E)-2-oxo-3-butenoic acid alkyl esters led
to diminished stereocontrol.
25
1
as off-white solid. [α]D = +217 (c 1.06, CH2Cl2); H NMR (600
MHz, CDCl3) δ 8.82 (d, J = 4.6 Hz, 2H), 7.94 (d, J = 9.1 Hz, 2H),
7.75 (s, 2H), 7.65 (d, J = 4.6 Hz, 2H), 7.33 (d, J = 2.1 Hz, 2H), 7.25
(dd, J = 9.1, 2.1 Hz, 2H), 6.41 (d, J = 10.9 Hz, 2H), 5.87 (ddd, J =
17.2, 10.0, 7.3 Hz, 2H), 5.07 (d, J = 17.2 Hz, 2H), 5.05 (d, J = 10.0 Hz,
2H), 3.87 (q, J = 9.2 Hz, 2H) 3.83 (s, 6H), 3.16 (dd, J = 13.4, 10.2 Hz,
2H), 2.84−2.89 (m, 4H), 2.59−2.65 (m, 2H), 2.30−2.33 (m, 2H),
1.81−1.83 (m, 2H), 1.70−1.75 (m, 4H), 1.33−1.38 (m, 2H). 13C
NMR (151 MHz, CDCl3) δ 158.5, 147.6, 145.1, 141.5, 140.4, 139.1,
132.1, 127.9, 122.2, 119.9, 119.5, 115.1, 100.2, 61.6, 57.1, 56.9, 55.8,
41.4, 39.4, 27.7, 27.3, 25.2. HR-MS (ESI-TOF) m/z calculated for
[C44H48N10O2+H]+: 749.4034; found: 749.4031
Scheme 3. Michael Addition of 1,3-Cyclohexanedione
Catalyzed by an in situ Formed eQN-2/Cu(OTf)2 Complex
1,1′-Di((8R,9R)-10,11-dihydro-6′-methoxycinchonan-9-yl)-
4,4′-bi-1,2,3-triazole (eDHQD-2). Following the general procedure,
starting from 9R-azido-9-deoxy-10,11-dihydroquinidine (eDHQD-1,
828 mg, 2.35 mmol), 628 mg of product (78%) was obtained after
25
chromatography (CHCl3/MeOH 15:1 v/v) as white solid. [α]D
=
1
+258 (c 1.04, CH2Cl2); H NMR (600 MHz, CDCl3) δ 8.77 (d, J =
4.6 Hz, 2H), 8.00 (d, J = 9.2 Hz, 2H), 7.98 (s, 2H), 7.50 (d, J = 4.6 Hz,
2H), 7.48 (d J = 2.6 Hz, 2H), 7.34 (dd, J = 9.2, 2.6 Hz, 2H), 6.43 (d, J
= 11.0 Hz, 2H), 3.91 (s, 6H), 3.78−3.83 (m, 2H), 2.92 (dd, J = 14.2,
9.3 Hz, 2H), 2.85−2.90 (m, 2H), 2.78−2.83 (m, 2H), 2.70−2.74 (m,
2H), 1.60−1.65 (m, 4H), 1.48−1.53 (m, 2H), 1.41−1.46 (m, 4H),
1.35−1.40 (m, 2H), 1.27−1.34 (m, 2H), 1.16−1.21 (m, 2H), 0.86 (t, J
= 7.3 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 158.8, 147.5, 145.1,
140.1, 139.4, 132.2, 128.2, 122.5, 119.4 (2C overlapped), 100.6, 59.9,
58.4, 55.8, 49.64, 49.59, 37.5, 27.5, 26.4, 26.1, 26.0, 12.1. HR-MS (ESI-
TOF) m/z calculated for [C44H52N10O2+H]+: 753.4347; found:
753.4354
All these results prove the applicability of an easily obtainable
chiral bitriazole system for copper-catalyzed transformations.
The failure of structurally similar phthalazine dimers suggests
that the bitriazole is a likely coordinating site, rather than just a
spacer which forms a distant environment for other catalytically
active sites. Without significant loss of selectivity, the system
could neither be simplified to a single triazole unit nor
expanded with additional rings separating the system.
EXPERIMENTAL SECTION
1,1′-Di((8R,9S)-10,11-dihydro-6′-methoxycinchonan-9-yl)-
4,4′-bi-1,2,3-triazole (DHQD-2). Following the general procedure,
starting from 9S-azido-9-deoxy-10,11-dihydroquinidine (DHQD-1,
■
General Procedure for Bitriazole Dimers 2. The appropriate 9-
azido-9-deoxy-alkaloid16 (1.25 mmol, 1 equiv) and 1,4-bis-
(trimethylsilyl)-1,3-butadiyne (125 mg, 0.64 mmol, 0.51 equiv) were
suspended in a mixture of tert-butanol (2 mL) and water (1 mL).
Pyridine (0.2 mL) was added followed by CuSO4·5H2O (51 mg, 0.2
mmol, 0.16 equiv), sodium ascorbate (0.13 g, 0.65 mmol, 0.52 equiv),
and potassium carbonate (0.14 g, 1.0 mmol, 0.8 equiv). After addition
the mixture turned yellow, then brown, and finally formed a red gel.
After 18 h of stirring, the mixture was diluted with dichloromethane (5
mL) and aqueous ammonia (25% soln., 0.5 mL) and stirred for an
additional 12 h. Then, a solution of sodium sulfide (satd. aqueous, 0.2
mL) was added, and after 5 min the mixture passed through a pad of
silica gel and washed with chlorofom/methanol (10:1 v/v, 50 mL),
and evaporated giving crude material rich in 2. The products were
purified on silica gel (chlorofom/methanol 15:1 or 20:1 v/v) to give
white or off-white crystalline solids. On heating at above 160 °C, the
products 2 undergo visible transition to semisolids and then melt with
decomposition in broad temperature ranges. Recrystallization
(MeOH) did not affect this behavior.
500 mg, 1.42 mmol), 251 mg of product (47%) was obtained after
25
chromatography (CHCl3/MeOH 15:1 v/v) as white solid. [α]D
=
−93 (c 1.06, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 8.82 (d, J = 4.6
Hz, 2H), 7.94 (d, J = 9.1 Hz, 2H), 7.74 (s, 2H), 7.61 (d, J = 4.5 Hz,
2H), 7.32 (d J = 2.0 Hz, 2H), 7.25 (dd, J = 9.1, 2.0 Hz, 2H), 6.39 (d, J
= 11.1 Hz, 2H), 3.74−3.90 (m, 2H), 3.83 (s, 6H), 3.05 (t, J = 11.6 Hz,
2H), 2.90−2.78 (m, 4H), 2.41 (d, J = 8.7 Hz, 2H), 1.69 (s, 2H), 1.64
(t, J = 9.4 Hz, 2H), 1.61−1.51 (m, 4H), 1.48−1.38 (m, 6H), 1.16−
1.09 (m, 2H), 0.86 (t, J = 6.7 Hz, 6H). 13C NMR (151 MHz, CDCl3)
δ 158.4, 147.5, 145.0, 140.3, 139.5, 132.0, 127.9, 122.1, 119.48, 119.44,
100.4, 60.9, 57.3, 55.7, 49.9, 49.2, 37.4, 27.1, 25.7, 25.4, 24.2, 11.9. HR-
MS (ESI-TOF) m/z calculated for [C44H52N10O2+H]+: 753.4347;
found: 753.4362
1,1′-Di((8S,9S)-cinchonan-9-yl)-4,4′-bi-1,2,3-triazole (eCD-2).
Following the general procedure, starting from 9S-azido-9-deoxy-
cinchonidine (eCD-1, 511 mg, 1.60 mmol), 400 mg of product (67%)
was obtained after chromatography (CHCl3/MeOH 20:1 v/v) as
25
1
white solid. [α]D = −107 (c 0.95, CH2Cl2); H NMR (600 MHz,
CDCl3, 318 K) δ 8.93 (d, J = 4.4 Hz, 2H), 8.29 (d, J = 8.5 Hz, 2H),
8.12 (d, J = 8.5 Hz, 2H), 8.07 (s, 2H), 7.67−7.70 (m, 2H), 7.54−7.58
(m, 4H), 6.52 (d, J = 11.4 Hz, 2H), 5.86 (ddd, J = 17.2, 10.6, 7.3 Hz,
2H), 5.03−5.06 (m, 4H), 3.86−3.91 (m, 2H), 3.31−3.37 (m, 2H),
3.12 (dd, J = 13.9, 10.5 Hz, 2H), 2.65−2.73 (m, 4H), 2.28 (br. s, 2H),
1.77−1.81 (m, 2H), 1.72 (br. s, 2H), 1.52−1.60 (m, 4H), 0.84 (dd, J =
13.3, 7.7 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 150.2, 148.9, 141.5,
140.8, 140.0, 130.8, 129.8, 127.9, 127.0, 122.6, 119.6, 119.4, 114.9,
60.1, 58.4, 56.1, 41.1, 39.3, 27.8, 27.7, 27.3. HR-MS (ESI-TOF) m/z
calculated for [C42H44N10+H]+: 689.3823; found: 689.3823
1,1′-Di((8S,9S)-6′-methoxycinchonan-9-yl)-4,4′-bi-1,2,3-tria-
zole (eQN-2). Following the general procedure, starting from 9-epi-9-
azido-9-deoxy-quinine16 (eQN-1, 0.436 g, 1.25 mmol), the crude
product of approximately 95% purity (NMR), was purified on silica gel
(CHCl3/MeOH 15:1 v/v) to give 409 mg (88%) as white crystalline
solid. [α]D25 = −205 (c 0.98, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ
8.76 (d, J = 4.5 Hz, 2H), 7.96 (d, J = 9.2 Hz, 2H), 7.94 (br. s, 2H),
7.49 (s, 2H), 7.44 (d, J = 4.5 Hz, 2H), 7.29 (d, J = 9.2 Hz, 2H), 6.42
(d, J = 11.1 Hz, 2H), 5.83−5.89 (m, 2H), 5.03 (d, J = 11.4 Hz, 2H),
5.03 (d, J = 16.2 Hz, 2H), 3.84 (s, 6H), 3.80−3.85 (m, 2H), 3.35−3.41
(m, 2H), 3.09 (dd, J = 13.6, 10.5 Hz, 2H), 2.58−2.68 (m, 4H), 2.25
(br. s, 2H), 1.86−1.92 (m, 2H), 1.70 (br. s, 2H), 1.49−1.56 (m, 4H),
0.84−0.88 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 158.6, 147.3,
145.0, 141.4, 140.0, 138.8, 132.0, 128.2, 122.4, 119.23, 119.16, 114.7,
100.8, 60.8, 57.9, 56.1, 55.8, 41.0, 39.2, 27.73, 27.72, 27.64. HR-MS
(ESI-TOF) m/z calculated for [C44H48N10O2+H]+: 749.4034; found:
749.4032
1,1′-Di((8R,9S)-10,11-dihydrocinchonan-9-yl)-4,4′-bi-1,2,3-
triazole (DHCN-2). Following the general procedure, starting from
9S-azido-9-deoxy-10,11-dihydrocinchonine (DHCN-1, 181 mg, 0.56
mmol), 42 mg of product (22%) was obtained after chromatography
1
(CHCl3/MeOH 20:1 v/v) as off-white solid. H NMR (600 MHz,
CDCl3) δ 9.00 (d, J = 4.4 Hz, 2H), 8.19 (d, J = 8.6 Hz, 2H), 8.11 (d, J
D
DOI: 10.1021/acs.joc.6b01403
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The Journal of Organic Chemistry
Note
= 8.5 Hz, 2H), 7.89 (s, 2H), 7.71 (d, J = 4.4 Hz, 2H), 7.67 (t, J = 7.7
Hz, 2H), 7.54 (t, J = 7.7 Hz, 2H), 6.53 (d, J = 10.9 Hz, 2H), 3.91−3.96
(m, 2H), 3.03 (t, J = 11.4 Hz, 2H), 2.79−2.89 (m, 4H), 2.40−2.44 (m,
2H), 1.72 (br. s, 2H), 1.20−1.70 (m, 12H), 0.85−0.93 (m, 8H). 13C
NMR (151 MHz, CDCl3) δ 150.3, 149.0, 141.7, 140.2, 130.8, 129.5,
127.6, 126.9, 122.2, 119.8, 119.3, 60.6, 57.7, 50.0, 49.4, 37.5, 29.8, 27.2,
25.8, 25.6, 24.6, 12.0. HR-MS (ESI-TOF) m/z calculated for
[C42H48N10+H]+: 693.4136; found: 693.4130
(c 0.90, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 8.81 (d, J = 4.6 Hz,
2H), 8.00 (d, J = 9.2 Hz, 2H), 7.60 (br. s, 2H), 7.53 (d, J = 2.7 Hz,
2H), 7.51 (d, J = 4.6 Hz, 2H), 7.34 (dd, J = 9.2, 2.6 Hz, 2H), 7.15 (s,
2H), 6.42 (d, J = 11.1 Hz, 2H), 5.88 (ddd, J = 17.4, 9.9, 7.0 Hz, 2H),
5.04−5.07 (m, 4H), 3.91−3.96 (m, 2H), 3.91 (s, 6H), 3.39−3.45 (m,
2H), 3.15 (dd, J = 14.0, 10.2 Hz, 2H), 2.68−2.75 (m, 4H), 2.27−2.32
(m, 2H), 1.87−1.91 (m, 2H), 1.73−1.76 (m, 2H), 1.53−1.63 (m, 4H),
0.85−0.90 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 158.8, 147.4,
145.1, 142.6, 141.4, 139.0, 132.4, 132.1, 128.3, 124.5, 122.5, 119.5,
117.8, 114.9, 100.9, 60.9, 58.0, 56.1, 55.9, 41.1, 39.2, 27.74, 27.73, 27.6.
HR-MS (ESI-TOF) m/z calculated for [C48H50N10O2S+H]+:
831.3912; found: 831.3902
1,2-Di(1-((8S,9S)-6′-methoxycinchonan-9-yl)-1,2,3-triazol-4-
yl)benzene (eQN-3). 9-Epi-9-azido-9-deoxy-quinine (eQN-1, 1.40 g,
4.01 mmol) and 1,2-bis(trimethylsilylethynyl)-benzene (515 mg, 1.91
mmol, 0.477 equiv) were suspended in a mixture of tert-butanol (20
mL) and water (10 mL). Pyridine (0.4 mL) was added followed by
CuSO4·5H2O (338 mg), sodium ascorbate (0.84 g), and potassium
carbonate (1.06 g). After addition the mixture turned into brown
suspension. After 2 days of stirring, aqueous ammonia (25% soln., 1
mL) was added and the mixture stirred for another 3 h. Solution of
sodium sulfide (satd. aqueous, 0.2 mL) was added, the mixture was
extracted with CH2Cl2 and passed through a pad of silica gel and
washed with chloroform. Subsequent purification on a silica gel
column (CHCl3/MeOH 15:1 v/v) gave 1.30 g (83%) of brown
1,8-Di(1-((8S,9S)-6′-methoxycinchonan-9-yl)-1,2,3-triazol-4-
yl)naphthalene (eQN-6). 9-Epi-azido-9-deoxy-quinine (eQN-1 973
mg, 2.78 mmol, 2.04 equiv) and 1,8-bis(trimethylsilylethynyl)-
naphthalene19 (435 mg, 1.36 mmol) were suspended in a mixture of
tert-butanol (15 mL) and water (7 mL). Pyridine (0.3 mL) was added
followed by CuSO4·5H2O (221 mg), sodium ascorbate (0.62 g), and
potassium carbonate (0.83 g). After 2 days of stirring, aqueous
ammonia (25% soln., 1 mL) was added and the mixture stirred for
another 3 h. Solution of Na2S (satd. aqueous, 0.2 mL) was added, the
mixture was extracted with CH2Cl2, passed through a pad of silica gel,
washed with chloroform, and evaporated to give 1.15 g of crude
material. Subsequent purification on a silica gel column (CHCl3/
MeOH 15:1 v/v) gave 1.10 g of off-white amorphous solid (92%).
25
amorphous solid. mp 141−148 °C (dec); [α]D = −160 (c 0.091,
1
CH2Cl2); H NMR (600 MHz, CDCl3) δ 8.77 (d, J = 4.5 Hz, 2H),
8.04 (d, J = 9.2 Hz, 2H), 7.98 (s, 2H), 7.49 (s, 2H), 7.63 (dd, J = 5.8,
3.4 Hz, 2H), 7.51 (br., 2H), 7.40 (dd, J = 9.1, 2.6 Hz, 2H), 7.30 (dd, J
= 5.8, 3.4 Hz, 2H), 6.31 (br., 2H), 5.84 (ddd, J = 17.4, 10.0, 7.2 Hz,
2H), 5.04−5.07 (m, 4H), 3.95 (s, 6H), 3.81−3.90 (m, 2H), 3.23−3.30
(m, 2H), 2.97 (dd, J = 13.7, 10.2 Hz, 2H), 2.64−2.71 (m, 2H), 2.54−
2.59 (m, 2H), 2.23−2.27 (m, 2H), 1.69−1.75 (m, 4H), 1.50−1.60 (m,
4H), 0.83−0.87 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 158.6,
147.5, 146.3, 145.0, 141.3, 139.6, 132.2, 130.4, 129.2, 128.2, 128.0,
122.4, 122.1, 119.9, 114.8, 101.0, 60.4, 58.4, 55.9, 55.8, 41.1, 39.2, 27.8,
27.6, 26.8. HR-MS (ESI-TOF) m/z calculated for [C50H52N10O2+H]+:
825.4347; found: 825.4339
25
1
[α]D = −43 (c 1.14, CH2Cl2); H NMR (600 MHz, CDCl3) δ 8.57
(br., 2H), 7.87−7.82 (m, 4H), 7.68 (br., 2H), 7.55−7.58 (m, 2H), 7.37
(br., 2H), 7.28 (br., 2H), 7.20 (br., 2H), 6.67 (br., 2H), 6.11 (br., 2H),
5.49 (br., 2H), 4.76−4.83 (m, 4H), 4.00 (s, 6H), 3.12 (br., 2H), 2.77−
2.95 (m, 4H), 2.43 (br., 2H), 2.27 (br., 2H), 2.03 (br., 2H), 1.44 (s,
2H), 1.37 (br. 4H) 1.06 (br., 2H), 0.56 (br., 2H). 13C NMR (151
MHz, CDCl3, 315 K) δ 158.4, 147.8, 147.0, 144.3, 141.1, 139.3, 135.1,
132.0, 131.0, 129.6, 128.9, 128.2, 127.1, 125.6, 124.1, 121.7, 120.2,
114.5, 100.6, 59.6, 59.3, 55.7, 55.6, 40.8, 39.1, 27.8, 27.4, 25.5. (1 C-sp2
not observed due to overlap). HR-MS (ESI-TOF) m/z calculated for
[C54H54N10O2+H]+: 875.4504; found: 875.4513
2,6-Di(1-((8S,9S)-6′-methoxycinchonan-9-yl)-1,2,3-triazol-4-
yl)pyridine (eQN-4). 2,6-Diethynylpyridine19 (134 mg, 1.06 mmol,
0.49 equiv) and 9-epi-9-azido-9-deoxy-quinine (eQN-1, 749 mg, 2.14
mmol) were dissolved in THF (10 mL), CuI (12 mg) was added, and
the mixture was stirred for 48 h. Then the mixture was diluted with
CH2Cl2 and a saturated aqueous solution of Na2S (2 drops) was
added. The mixture was washed with water, extracted with CH2Cl2,
dried over Na2SO4, and evaporated. The mixture was filtered through
silica gel (CHCl3/MeOH 20:1). Obtained 883 mg >99%. mp 205−
(8S,9S)-6′-Methoxy-9-(4-trimethylsilyl-1,2,3-triazol-1-yl)-
cinchonan (eQN-7). To a solution of 9-epi-azido-9-deoxy-quinine
(eQN-1 1.38 g, 3.97 mmol) in MeOH (20 mL) were added water (9
mL), TMS-acetylene (1 mL, 7.08 mmol, 1.78 equiv), copper sulfate
pentahydrate (36 mg), and sodium ascorbate (0.3 g). The mixture was
stirred at room temperature for 24 h and then saturated Na2S solution
was added (2 drops). The mixture was concentrated in vacuo, the
residue was suspended in CH2Cl2, was dried over MgSO4, and was
passed through a plug of silica gel. On evaporation 1.74 g of pure
eQN-7 was obtained (98%) as white slowly crystallizing solid. mp
22
215 °C. [α]D = −213 (c 1.00, CH2Cl2); 1H NMR (600 MHz,
CDCl3) δ 8.78 (br., 2H), 7.94−8.05 (m, 6H), 7.65 (br., 1H), 7.49 (s,
2H), 7.38 (br., 2H), 7.32 (d, J = 8.9 Hz, 2H), 6.41 (br., 2H), 5.81−
5.87 (m, 2H), 5.08 (d, J = 10.5 Hz, 2H), 5.04 (d, J = 17.1 Hz, 2H),
3.92 (s, 6H), 3.79 (br., 2H), 3.42 (br., 2H), 2.99 (br., 2H), 2.47−2.68
(m, 4H), 2.24 (br., 2H), 1.89 (br., 2H), 1.72 (s, 2H), 1.55 (br., 4H),
0.84 (br., 2H). 13C NMR (151 MHz, CDCl3) δ 158.8, 150.1, 148.0,
147.3, 145.0, 141.4, 138.6, 137.7, 131.9, 128.3, 122.6, 120.6, 119.6,
119.3, 114.9, 100.8, 60.9, 57.9, 55.97, 55.94, 41.0, 39.1, 27.79, 27.71,
27.69. HR-MS (ESI-TOF) m/z calculated for [C49H51N11O2+H]+:
826.4300; found: 826.4291
23
1
180−182 °C; [α]D = −115 (c 1.00, CH2Cl2); H NMR (600 MHz,
CDCl3) δ 8.81 (d, J = 4.5 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.56 (br.,
1H), 7.51 (d, J = 4.5 Hz, 1H), 7.43 (s, 1H), 7.39 (dd, J = 9.3, 2.7 Hz,
1H), 6.60 (br., 1H), 5.92 (ddd, J = 17.4, 10.0, 7.0 Hz, 1H), 5.10−5.13
(m, 2H), 4.07 (br., 1H), 3.97 (s, 3H), 3.37−3.43 (m, 1H), 3.24 (dd, J
= 13.8, 10.5 Hz, 1H), 2.78−2.91 (m, 2H), 2.39 (br. s, 1H), 1.93−1.98
(m, 1H), 1.82 (br. s, 1H), 1.59−1.64 (m, 2H), 0.98−1.06 (br., 1H),
0.22 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 158.6, 147.4, 146.4,
145.0, 141.5, 139.8, 131.9, 128.3, 127.3, 122.4, 119.5, 114.7, 100.9,
60.1, 58.1, 56.0, 55.8, 41.0, 39.2, 27.79, 27.73, 27.5, −1.0. HR-MS
(ESI-TOF) m/z calculated for [C25H33N5OSi+H]+: 448.2527; found:
448.2511
2,4-Di(1-((8S,9S)-6′-methoxycinchonan-9-yl)-1,2,3-triazol-4-
yl)thiophene (eQN-5). 9-Epi-9-azido-9-deoxy-quinine (eQN-1 1.86
g, 5.33 mmol) and 2,5-bis(trimethylsilylethynyl)-thiophene18 (0.574 g,
2.08 mmol, 0.39 equiv) were suspended in a mixture of tert-butanol
(25 mL) and water (15 mL). Pyridine (0.4 mL) was added followed by
CuSO4·5H2O (382 mg), sodium ascorbate (0.84 g), and potassium
carbonate (1.43 g). After addition the mixture turned into orange
suspension, and after 2 days became yellowish-gray. Then aqueous
ammonia (25% soln., 1 mL) was added and the mixture stirred for
another 3 h. Solution of sodium sulfide (satd. aqueous, 0.2 mL) was
added, and after 5 min the mixture passed through a pad of silica gel
and was washed with CHCl3/MeOH (10:1 v/v, 50 mL), was
evaporated, and was purified on silica gel (CHCl3/MeOH 20:1 v/v). A
portion of crude material was purified by crystallization in Soxhlet
apparatus from methanol. A total of 1.78 g (99%) of white crystalline
product was obtained. mp 274−276 °C (dec, MeOH). [α]D25 = −288
(8S,9S)-6′-Methoxy-9-(1,2,3-triazol-1-yl)cinchonan (eQN-8).
In a polypropylene tube TMS-protected compound eQN-7 (100
mg, 0.22 mmol) was dissolved in a solution of hydrofluoric acid
(prepared by dissolving 0.2 mL of 40% aqueous HF in 2 mL of
methanol). After 4 h aqueous sodium bicarbonate was added and the
mixture extracted with CH2Cl2. The combined organic phases were
dried and evaporated to yield 75 mg (90%) pure eQN-8 as an off-
25
1
white solid. mp 167−169 °C; [α]D = −34 (c 1.09, CH2Cl2); H
NMR (600 MHz, CDCl3) δ 8.80 (d, J = 4.5 Hz, 1H), 8.01 (d, J = 9.2
Hz, 1H), 7.59 (d, J = 0.7 Hz, 1H), 7.51 (br., 2H), 7.49 (d, J = 4.5 Hz,
1H), 7.36 (dd, J = 9.2, 2.6 Hz, 1H), 6.50 (d, J = 11.1 Hz, 1H), 5.91
(ddd, J = 17.3, 10.0, 7.0 Hz, 1H), 5.07−5.10 (m, 2H), 3.94−3.99 (m,
E
DOI: 10.1021/acs.joc.6b01403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1H), 3.93 (s, 3H), 3.43−3.49 (m, 1H), 3.21 (dd, J = 14.1, 10.2 Hz,
1H), 2.72−2.80 (m, 2H), 2.32−2.37 (m, 1H), 1.89−1.95 (m, 1H),
1.79 (sext, J = 3.0 Hz, 1H), 1.57−1.67 (m, 2H), 0.92−0.96 (m, 1H).
13C NMR (151 MHz, CDCl3) δ 158.8, 147.5, 145.2, 141.4, 139.2,
(2) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M. J.
Org. Chem. 1992, 57, 2768−2771.
(3) Crispino, G. A.; Jeong, K. S.; Kolb, H. C.; Wang, Z. M.; Xu, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785−3786.
(4) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35,
448−451.
(5) Cinchona alkaloids in Synthesis and Catalysis: Ligands, Immobiliza-
tion and Organocatalysis; Song, C. E., Ed.; Wiley-VCH: Wienheim,
Germany, 2009.
134.0, 132.2, 128.3, 122.5, 122.1, 119.4, 115.0, 100.9, 60.7, 58.2, 56.2,
55.9, 41.2, 39.2, 27.79, 27.77, 27.65. HR-MS (ESI-TOF) m/z
calculated for [C22H25N5O+H]+: 376.2132; found: 376.2147
General Procedure for Asymmetric Michael Addition−
Cyclization Reaction. Ligand (10 mol%, 0.025 mmol) and
copper(II) triflate (9.0 mg, 0.025 mmol, 10 mol%) were suspended
in dichloromethane (1.0 mL) and the resulting light blue quasi-
homogeneous solution was stirred for 1.5 h at 20 °C. Michael acceptor
9 (0.25 mmol, 1.0 equiv) was added and the mixture was stirred for
another 0.5 h at 20 °C and the color turned light yellow to green.
Finally, dimedone or 1,3-cyclohexanedione (0.25 mmol, 1.0 equiv) in
0.5 mL of dichloromethane were added, resulting in a homogeneous
solution and color change to deep green or reddish. In case of 1,3-
cyclohexanedione a precipitate appears after a few hours. The reaction
was run for 48 h at 17−20 °C, then diluted by AcOEt (5 mL), and
filtered through a pad of silica gel eluting with a total volume of 150
mL AcOEt. The filtrate was evaporated in vacuo. Crude products were
analyzed by HPLC. Pure samples were obtained after chromatography
(silica gel, 35−40 g, hexanes/AcOEt 3:1 to 2:1, v/v) as colorless oils
that transformed to amorphous solids. The absolute configuration of
products were determined by comparison of the sign of the [α]D and
order of elution in HPLC with the literature data (For the details, see
SI).25
Ethyl 4-(2-Hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-4-
(4-methoxy-phenyl)-2-oxobutyrate (10). Following the general
procedure using eQN-2 as ligand, 52 mg (62%) of colorless oil was
obtained. The enantiomeric excess was determined by analytical
HPLC (Chiralpak AD column, 70:30 hexanes:isopropanol, 0.7 mL/
min, λ 254 nm) tr (4R) = 6.7 min, tr (4S) = 9.7 min, ee =73%: [α]D =
−7.0 (c 0.6, CH2Cl2).
Ethyl 2-Hydroxy-3,4,5,6,7,8-hexahydro-5-oxo-4-phenyl-2H-
chromene-2-carboxylate (11). Following general procedure using
eQN-2 as ligand, 58 mg (73%) of colorless oil was obtained. The
enantiomeric excess was determined by analytical HPLC (Chiralpak
AD column, 80:20 hexanes:isopropanol, 0.75 mL/min, λ 254 nm) tr
(4R) = 9.9 min, tr (4S) = 13.3 min, ee =82%: [α]D = +17.5 (c 1.0,
CH2Cl2).
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spontaneously form triazolidine; see ref 16.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01403.
1
Supporting tables, H and 13C NMR spectra for new
compounds, chromatograms for 10 and 11, and
computational details for eQN-2 (PDF)
(25) Calter, P. A.; Wang, J. Org. Lett. 2009, 11, 2205−2208.
(26) Chen, X.; Zheng, C.; Zhao, S.; Chai, Z.; Yang, Y.; Zhao, G.; Cao,
W. Adv. Synth. Catal. 2010, 352, 1648−1652.
(27) Gao, Y.; Ren, Q.; Ang, S.; Wang, J. Org. Biomol. Chem. 2011, 9,
3691−3697.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: przemyslaw.boratynski@pwr.wroc.pl
(28) Wang, Y.; Wang, K.; Zhang, W.; Zhang, B.; Zhang, C.; Xu, D.
Eur. J. Org. Chem. 2012, 2012, 3691−3696.
Notes
(29) For metal catalysis, see: Halland, N.; Velgaard, T.; Jorgensen, K.
̈
The authors declare no competing financial interest.
A. J. Org. Chem. 2003, 68, 5067−5074.
(30) Dong, Z.; Feng, J.; Fu, X.; Liu, X.; Lin, L.; Feng, X. Chem. - Eur.
J. 2011, 17, 1118−1121.
ACKNOWLEDGMENTS
■
(31) For asymmetric synthesis of biologically importatnt chromans
and other six-membered oxygenated systems, see: Shen, H. C.
Tetrahedron 2009, 65, 3931−3952.
We are grateful to the National Science Center (NCN) Poland
for funding (Grant No. 2013/11/D/ST5/02909) and to the
Wrocław Center for Networking and Supercomputing for
allotment of computer time (No. 362). We also thank Mr.
Kamil Turkowiak for obtaining DHQD-2.
(32) Nunez, M. G.; García, P.; Moro, R. F.; Díez, D. Tetrahedron
́
̃
2010, 66, 2089−2109.
(33) For applications of α-oxoesters in the synthesis of heterocycles,
see: Eftekhari-Sis, B.; Zirak, M. Chem. Rev. 2015, 115, 151−264.
(34) Rong, C.; Pan, H.; Liu, M.; Tian, H.; Shi, Y. Chem. - Eur. J. 2016,
22, 2887−2891.
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DOI: 10.1021/acs.joc.6b01403
J. Org. Chem. XXXX, XXX, XXX−XXX